Plasmodium falciparum malaria afflicts up to 10% of the global population, resulting in over 600 million infections and two to three million deaths annually. Malaria-related fatalities arise predominantly from two clinically defined complications associated with severe disease: cerebral malaria (CM) and severe malaria anemia (SMA). Substantial scientific evidence indicates that severe malarial disease results from the downstream effects of a toxin generated by the malaria parasite. This toxin, a glycolipid termed glycosylphosphatidylinositol (GPI), leads to excessive inflammatory cytokine production and, hence, the clinical manifestations observed in both CM and SMA. Published pre-clinical studies demonstrate that the glycan (carbohydrate) portion of the GPI can provide immunoprotection against CM caused by a malaria species within an established murine model. Recently, rodent models for SMA have been developed, which parallel the SMA clinically observed in humans upon malaria infection. Moreover, the models display one or both of the anemia forming mechanisms observed in human clinical disease: uninfected red blood cell clearance and erythropoietic suppression. The overall goals of this proposal are: to evaluate if immunization towards the GPI glycan can confer protection against SMA in the recently developed animal models, to identify a lead product candidate to move into development, and to begin to validate anemia as a potential clinical endpoint in detailed anemia characterization studies. PUBLIC HEALTH RELEVANCE: Ancora Pharmaceuticals Inc. is developing a novel vaccine against malaria. Severe anemia is a major complication due to malaria infection, especially in young children. This proposal aims to provide key proof-of-concept data that the anti-toxin vaccine approach may protect against severe malaria anemia.